Traditionally, dramatic improvements in the treatment of cancer are associated with identification of therapeutic agents acting through novel mechanisms. One mechanism that has been exploited in cancer treatment is the modulation of protein kinase activity, because signal transduction through protein kinase activation is responsible for many of the characteristics of tumor cells. Protein kinase signal transduction is of particular relevance in, for example, thyroid, gastric, kidney, brain, head and neck, lung, breast, prostate and colorectal cancers, as well as in the growth and proliferation of brain tumor cells, among many other solid and blood cancers.
Protein kinases can be categorized as receptor type or non-receptor type. Receptor-type tyrosine kinases generally comprise of a transmenbrane receptors with diverse biological activities. For a detailed discussion of the receptor-type tyrosine kinases, see “Structural biology of protein tyrosine kinases”, Cell. Mol. Life Sci., 2006 (63), 2608-2625. Since kinases and their ligands play critical roles in various cellular activities, dysregulation of protein kinase activity can lead to altered cellular properties, such as uncontrolled cell growth associated with cancer. Therefore, protein kinases are attractive targets for small molecule drug discovery. Particularly attractive targets for small-molecule modulation with respect to antiangiogenic and antiproliferative activity include receptor tyrosine kinases such as VEGFRs, Flt3, c-Met, Axl and Mer, among many others.
Angiogenesis, the formation of new capillaries from preexisting blood vessels, is a necessary process for organ development during embryogenesis and is critical for the female reproductive cycle, inflammation, and wound healing in the adult. Certain diseases are known to be associated with dysregulated angiogenesis, for example ocular neovascularization, such as retinopathies (including diabetic retinopathy), age-related macular degeneration, fibrosis, psoriasis, hemangioblastoma, hemangioma, arteriosclerosis, inflammatory disease, such as a rheumatoid or rheumatic inflammatory disease, especially arthritis (including rheumatoid arthritis), or other chronic inflammatory disorders, such as chronic asthma, arterial or post-transplantational atherosclerosis, endometriosis, and neoplastic diseases, for example so-called solid tumors and liquid tumors (such as leukemias). Solid tumors, in particular, are dependent on angiogenesis to grow beyond a certain critical size by inducing new capillaries sprouting from existing blood vessels to secure their nutrition, oxygen supply, and waste removal. In addition, angiogenesis also promotes metastasis of tumor cells to other sites.
The new vessel growth and maturation are highly complex and coordinated processes, requiring the stimulation by a number of growth factors. Vascular endothelial growth factor (VEGF) signaling often represents a critical rate-limiting step in physiological and pathological angiogenesis. VEGF binds to and activates the receptor tyrosine kinase, VEGFR. Three VEGFR isoforms have been identified in humans: VEGFR-1 (Flt-1), VEGFR-2 (KDR/Flk-1) and VEGFR-3 (Flt-4). VEGFR-2 mediates the majority of cellular responses to VEGF, in particular its mitogenic and angiogenic effects. VEGFR-1 is thought to modulate VEGFR-2 signaling or to act as a dummy/decoy receptor to sequester VEGF away from VEGFR-2. (Stuttfeld E, Ballmer-Hofer K (2009). “Structure and function of VEGF receptors”. IUBMB Life 61 (9): 915-22.)
Since VEGFR-2 is the major mediator of vascular endothelial cell (EC) mitogenesis and survival, as well as angiogenesis and microvascular permeability, it is expected that direct inhibition of the kinase activity of VEGFR-2 will result in the reduction of angiogenesis and the suppression of tumor growth. Furthermore, inhibition of VEGFR-2 targeting the genetically more stable host endothelial cells, instead of labile tumor tissues, may decrease the chance of resistance development. Several agents targeting VEGFR signaling, administered either as single agents or in combination with chemotherapy, have been shown to benefit patients with advanced-stage malignancies. (“VEGF-targeted therapy: mechanisms of anti-tumor activity.” Nature Reviews Cancer, 2008, 8, 579; “Molecular basis for sunitinib efficacy and future clinical development.” Nature Reviews Drug Discovery, 2007, 6, 734; “Angiogenesis: an organizing principle for drug discovery?” Nature Reviews Drug Discovery, 2007, 6, 273).
FLT3 (Flt3, FMS-related tyrosine kinase 3), also known as FLK-2 (fetal liver kinase 2) and STK-1 (human stem cell kinase 1), belongs to a member of the class III receptor tyrosine kinase (RTK-III) family that include KIT, PDGFR, FMS and FLT1 (Stirewalt D L, et al., Nat. Rev Cancer, 2003, 3:650-665). FLT3 has been implicated in hematopoietic disorders which are pre-malignant disorders including myeloproliferative disorders, such as thrombocythemia, essential thrombocytosis (ET), myelofibrosis (MF), chronic idiopathic myelofibrosis (LMF), and polycythemia vera (PV), pre-malignant myelodysplastic syndromes. Hematological malignancies include leukemias, lymphomas (non-Hodgkin's lymphoma), Hodgkin's disease (also called Hodgkin's lymphoma), and myeloma, for instance, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL) (Matthew C. Stubbs and Scott A. Armstrong, “FLT3 as a Therapeutic Target in Childhood Acute Leukemia.” Current Drug Targets, 2007, 8, 703-714).
FLT3 is overexpressed at the levels in 70-100% of cases of acute myeloid leukemias (AML), and in a high percentage of T-acute lymphocytic leukemia (ALL) cases (Griffin J D, et al., Haematol J. 2004, 5: 188-190). It is also overexpressed in a smaller subset of chronic myeloid leukemia (CML) in blast crisis. Studies have shown that the leukemic cells of B lineage ALL and AML frequently co-express FL, setting up autocrine or paracrine signaling loops that result in the constitutive activation of FLT3 (Zheng R, et. al., Blood., 2004, 103: 267-274). A high level of the FLT3 ligand is found in the serum of patients with Langerhans cell histocytosis and systemic lupus erythematosus, which further implicates FLT3 signaling in the dysregulation of dendritic cell progenitors in those autoimmune diseases (Rolland et al., J. Immunol., 2005, 174:3067-3071; Engen et al., “Targeted Therapy of FLT3 in Treatment of AML—Current Status and Future Directions.” J. Clin. Med., 2014, 3, 1466-1489).
c-Met, also referred to as hepatocyte growth factor receptor (HGFR), is expressed predominantly in epithelial cells but has also been identified in endothelial cells, myoblasts, hematopoietic cells and motor neurons. The natural ligand for c-Met is hepatocyte growth factor (HGF), also known as scatter factor (SF). In both embryos and adults, activated c-Met promotes a morphogenetic program, known as invasive growth, which induces cell spreading, the disruption of intercellular contacts, and the migration of cells towards their surroundings. (“From Tpr-Met to Met, tumorigenesis and tubes.” Oncogene, 2007, 26, 1276; “Met Receptor Tyrosine Kinase as a Therapeutic Anticancer Target.” Cancer Letter, 2009, 280, 1-14).
A wide variety of human malignancies exhibit sustained c-Met stimulation, overexpression, or mutation, including carcinomas of the breast, liver, lung, ovary, kidney, thyroid, colon, renal, glioblastomas, and prostate, etc. c-Met is also implicated in atherosclerosis and organ fibrosis such as lung fibrosis. Invasive growth of certain cancer cells is drastically enhanced by tumor-stromal interactions involving the HGF/c-Met pathway. Thus, extensive evidence that c-Met signaling is involved in the progression and spread of several cancers has generated considerable interest in c-Met as major targets in cancer drug development. (“Molecular cancer therapy: can our expectation be MET.” Euro. J. Cancer, 2008, 44, 641-651; “Targeting the c-Met Signaling Pathway in Cancer.” Clin. Cancer Res., 2006, 12, 3657). Agents targeting c-Met signaling pathway are now under clinical investigation. (“Novel Therapeutic Inhibitors of the c-Met Signaling Pathway in Cancer.” Clinical Cancer Research, 2009, 15, 2207; “Drug development of MET inhibitors: targeting oncogene addiction and expedience.” Nature Review Drug Discovery, 2008, 7, 504).
The TYRO3, AXL (also known as UFO) and MERTK (also known as Mer) (TAM) family of receptor tyrosine kinases (RTKs) was one of the latest to evolve. Members of this family have a similar overall domain structure and are highly related by a unique KWIAIES conserved sequence in their kinase domain. TAM RTKs are ectopically expressed or overexpressed in a wide variety of human cancers in which they provide tumor cells with a survival advantage. In experimental models, Axl and MerTK can be oncogenic. Although MerTK and Axl can activate standard proliferative pathways (ERK, AKT and members of the signal transducer and activator of transcription (STAT) family), their output generally promotes survival rather than proliferation. These kinases are potentially dual anticancer targets, firstly in tumor cells that have developed a non-oncogene addiction to TAM RTK survival signals and secondly in the microenvironment where MerTK and Axl inhibition may reverse innate immune suppression. (“The TAM family: phosphatidylserine-sensing receptor tyrosine kinases gone awry in cancer.” Nature Review Cancer, 2014, 14, 769)
Recently a study showed that Mer and Axl were frequently overexpressed and activated in many tumor cell lines, such as in various NSCLC cell lines. Ligand-dependent Mer or Axl activation stimulated MAPK, AKT and FAK signaling pathways indicating roles for these RTKs in multiple oncogenic processes. Abnormal expression and activation of Axl knockdown also improved in vitro NSCLC sensitivity to chemotherapeutic agents by promoting apoptosis. When comparing the effects of Mer and Axl knockdown, Mer inhibition exhibited more complete blockade of tumor growth while Axl knockdown more robustly improved chemosensitivity. Therefore, inhibition of Axl, Mer or both is potentially a therapeutic strategy to target cancer cells (Rachel et al., “Mer or Axl Receptor Tyrosine Kinase inhibition promotes apoptosis, blocks growth, and enhances chemosensitivity of human non-small cell lung cancer” Oncogene, 2013, 32(29), 3420-3431).
Accordingly, small-molecule compounds that specially inhibit, regulate and/or modulate the signal transduction of kinases, particularly including VEGFRs, Flt3, c-Met, Axl and Mer as described above, are desirable as a means to treat or prevent disease states associated with abnormal cell proliferation and angiogenesis. One such small-molecule is N-(3-fluoro-4-((7-(2-hydroxy-2-methylpropoxy)quinolin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide, which has the chemical structure as shown in the following:

WO 2012118632 A1 described the synthesis of N-(3-fluoro-4-((7-(2-hydroxy-2-methylpropoxy)quinolin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (Example 1), the salts thereof, such as hydrochloride (Example 5), maleate (Example 6), p-toluenesulfonate (Example 7), and benzene sulfonate (Example 8), and also disclosed the therapeutic activity of these molecules and salts thereof in inhibiting, regulating and modulating the signal transduction of protein kinases.
Different salts and solid state form of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid state forms may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, improving the dissolution profile, stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of different salts and solid state forms may also provide improvements to the final dosage form, for example, if they serve to improve bioavailability. Different salts and solid state forms of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to assess variations in the properties and characteristics of a solid active pharmaceutical ingredient.